The hypothesis of this proposal is that optical coherence tomography (OCT), an emerging biomedical! diagnostic imaging technology for in situ imaging of tissue microstructure, can be developed and applied for "optical biopsy," the real time, in vivo detection of early neoplastic changes. Image guidance can be coupled with excisional biopsy to reduce sampling error and improve sensitivity. This program integrates new technology development with applications to biomedical and clinical studies. The specific aims are: 1. Develop ultrahigh resolution OCT and spectroscopic OCT technology, improving the current 10-15 um resolution to the 1-2 um level. This dramatic improvement in image resolution will significantly enhance the performance of OCT for imaging of architectural morphology and will facilitate the identification of early neoplastic changes such as dysplasia. Spectroscopic OCT imaging will improve differentiation of tissue based on spectroscopic properties and promises to provide assessment of cellular morphology. These studies will utilize state of the art laser technology developed in our group, enabling ultrahigh resolution imaging in broad wavelength regimes to optimize image penetration and resolution. 2. Develop new optical coherence microscopy (OCM) technology, which integrates OCT with confocal microscopy. OCM enables cellular level resolution and has image penetration depths greater than confocal microscopy. It also performs imaging without the need for high numerical apertures required in confocal microscopy, thus enabling imaging with small probes such as laparoscopes, endoscopes, and needles. 3. Investigate OCT imaging in normal animals and models of cancer progression. Imaging studies will be performed in the normal rabbit to validate new endoscopic imaging techniques. The hamster cheek pouch model of squamous cell carcinoma and the AOM rat model of colon cancer will be used to image cancer progression. 4. Investigate ultrahigh resolution OCT and spectroscopic OCT imaging of the GI tract. This aim will involve imaging of ex vivo specimens and endoscopic imaging studies. The feasibility of OCT imaging to differentiate short segment Barrett's esophagus, dysplasia and adenocarcinoma of the esophagus, and adenomatous vs. hyperplastic polyps in the colon will be explored. This program is a multidisciplinary collaborative effort with investigators at the VA Boston Healthcare system. If successful, this research will develop new imaging technology with applications in gastrointestinal endoscopy as well as the detection of a wide range of early neoplastic changes.